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INVITED REVIEW
Using magnetic resonance imaging to assess visual deficits: areviewHolly D. H. Brown1, Rachel L. Woodall1, Rebecca E. Kitching1, Heidi A. Baseler1,2 andAntony B. Morland1,2
1Department of Psychology, University of York, York, and 2Hull York Medical School, University of York, York, UK
Citation information: Brown HDH, Woodall RL, Kitching RE, Baseler HA & Morland AB. Using magnetic resonance imaging to assess visual deficits:
a review. Ophthalmic Physiol Opt 2016; 36: 240–265. doi: 10.1111/opo.12293
Keywords: albinism, amblyopia,
anophthalmia, functional magnetic resonance
imaging, glaucoma, macular degeneration,
magnetic resonance imaging, magnetic
resonance spectroscopy, ophthalmology, visual
deficit
Correspondence: Antony B Morland
E-mail address: [email protected]
Received: 23 December 2015; Accepted: 15
February 2016
Abstract
Purpose: Over the last two decades, magnetic resonance imaging (MRI) has been
widely used in neuroscience research to assess both structure and function in the
brain in health and disease. With regard to vision research, prior to the advent of
MRI, researchers relied on animal physiology and human post-mortem work to
assess the impact of eye disease on visual cortex and connecting structures. Using
MRI, researchers can non-invasively examine the effects of eye disease on the
whole visual pathway, including the lateral geniculate nucleus, striate and extras-
triate cortex. This review aims to summarise research using MRI to investigate
structural, chemical and functional effects of eye diseases, including: macular
degeneration, retinitis pigmentosa, glaucoma, albinism, and amblyopia.
Recent Findings: Structural MRI has demonstrated significant abnormalities
within both grey and white matter densities across both visual and non-visual
areas. Functional MRI studies have also provided extensive evidence of functional
changes throughout the whole of the visual pathway following visual loss, particu-
larly in amblyopia. MR spectroscopy techniques have also revealed several abnor-
malities in metabolite concentrations in both glaucoma and age-related macular
degeneration. GABA-edited MR spectroscopy on the other hand has identified
possible evidence of plasticity within visual cortex.
Summary: Collectively, using MRI to investigate the effects on the visual pathway
following disease and dysfunction has revealed a rich pattern of results allowing
for better characterisation of disease. In the future MRI will likely play an impor-
tant role in assessing the impact of eye disease on the visual pathway and how it
progresses over time.
Introduction
Magnetic resonance imaging (MRI) has transformed the
field of neuroscience, providing a non-invasive method to
evaluate the structure, function and neurochemistry of the
human brain. By correlating brain measures with beha-
vioural outcomes or clinical symptoms, neuroimaging
methods such as MRI have allowed researchers to make
inferences about the mechanisms underlying differences in
clinical presentation.
Approximately 20% of cortex in the human brain is ded-
icated to visual processing, spanning the occipital lobe and
extending into temporal and parietal regions.1 MRI can
reveal associated changes in the brain, particularly in the
visual pathways, to a number of visual disorders, including
anophthalmia, glaucoma and age-related macular degener-
ation (AMD). In the past, both structural and functional
MRI have been used to probe for evidence of reorganisa-
tion or degeneration in the human brain as a result of
diminished visual input. More recently, magnetic reso-
nance spectroscopy (MRS) has been used to investigate
neurochemical changes in visual cortex; changes in metabo-
lite concentrations can then be correlated with structural
and functional changes.
© 2016 The The Authors Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.
Ophthalmic & Physiological Optics 36 (2016) 240–265
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
240
Ophthalmic & Physiological Optics ISSN 0275-5408
In this review, we will focus on the structural, neuro-
chemical and functional MRI modalities and their contri-
bution to our understanding of the way in which the brain
responds to visual deficits.
Visual diseases and disorders
First, we will give a brief overview of several visual diseases
and disorders that have been investigated using MR imag-
ing methods. We order the deficits on the basis of an ante-
rior (eye/retina) to posterior (optic nerve/brain) scheme,
which we will also use in the review of imaging studies later
in the article. Throughout the review we describe studies of
individuals with visual field deficits (scotomas), which are
typically bilateral thereby removing input to visual cortex.
However, we also note where patients have unilateral dis-
ease and whether bilateral patients are tested monocularly.
Anophthalmia and early blindness
Anophthalmia is a rare condition whereby the eyes fail to
develop in utero and as a result, a child is born without
eyes, and there is therefore no means of light stimulation
reaching the visual areas of the brain. Anophthalmia is
likely to be caused by disturbances of the morphogenetic
pathway that controls eye development, either as a result of
primary genetic defect or external gestation factors which
can influence the smooth process of morphogenesis.2 The
incidence of anophthalmia is estimated to be 1.8 per
100 000 in the general population.3 The study of subjects
with anophthalmia provides a novel and scientifically
unique group to examine the structure, function and con-
nectivity of the occipital lobe.4 We will also review papers
on ‘early blindness’. This term captures a variety of causes
of visual loss that occur early in development.
Macular degeneration
Macular degeneration is a family of disorders and causes a
progressive loss of central vision by mainly affecting the
macula of the retina. Early-onset manifestations of the dis-
ease are usually inherited and are known as juvenile macu-
lar dystrophies, or juvenile macular dystrophy (JMD),
while late-onset forms of the disease primarily affect the
older population, and are known collectively as age-related
macular degeneration, or AMD. AMD is the leading cause
of vision loss in developed countries; in the UK, 12% of all
people over the age of 80 are affected by late stage AMD.
Most visual loss occurs in the late stages of AMD due to
one of two forms: neovascular, or ‘wet’ AMD or geographic
atrophy, or ‘dry’ AMD. Dry AMD is a progressive atrophy
of the retinal pigment epithelium (RPE), choriocapillaris
and photoreceptors.5 Dry AMD is also the most common
form of the disease, characterised by a central scotoma
caused by a build-up of drusen in the RPE. Drusen consists
of a build-up of waste products in the eye (such as choles-
terol and fatty substances) that would normally be released
in the healthy retina. This build-up damages the photore-
ceptors, thus leading to central blindness. Dry AMD is a
progressive disease for which currently there is no cure.
Neovascular-AMD (nvAMD) or ‘Wet’ AMD is the more
treatable form (most commonly using anti-vascular
endothelial growth factor drugs). In this form, blood, lipids
and fluid leak to cause a swelling under the macula. This
results in fibrous scarring caused by a breakthrough of new
blood vessel growth (choroidal neovascularisation) to the
neural retina. This scarring and choroidal neovascularisa-
tion damages central vision, progressing to form a central
scotoma or distortion of straight lines (metamorphopsia)
or both. In the UK, nvAMD accounts for more than half of
all cases of registered sight and severe sight impairment.6
Retinitis pigmentosa
Retinitis pigmentosa (RP) is a group of hereditary visual
dystrophies, affecting 1 in 4000 individuals, and is the lead-
ing inherited cause of blindness.7, 8 RP is characterised by
the progressive loss of both rod and cone photoreceptors
and primarily occurs within the peripheral region before
developing in the fovea.9 Although there is currently no
cure for the disease, an intervention study has shown a
decline in disease progression following vitamin A and vita-
min E supplements.10 Recent studies have also examined
the potential of retinal implants11–13 and gene-therapy14, 15
to restore visual function.
Glaucoma
Glaucoma is the second most common cause of blindness
worldwide. It is essentially a collection of neurodegenera-
tive diseases caused initially by damage to the optic nerve,
affecting both the retina and the central visual pathway.16 It
can ultimately lead to degenerative changes in the lateral
geniculate nucleus (LGN) and visual cortex. However, glau-
coma is described as one of the preventable causes of blind-
ness if diagnosed early.
In glaucoma, visual field loss typically starts peripherally.
It is often (but not always) associated with elevated intra-
ocular pressure (IOP), causing progressive retinal ganglion
cell loss and optic nerve damage resulting in the loss of par-
afoveal and peripheral vision.17–20 Alarmingly, glaucoma
often goes unnoticed and over 50% of ganglion cells may
have already died by the time advanced symptoms are pre-
sent and a diagnosis is made.21 Glaucoma has been shown
to affect the whole visual pathway, extending from the
retina to the optic nerve, LGN and visual cortex, causing
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Ophthalmic & Physiological Optics 36 (2016) 240–265
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H D H Brown et al. Using MRI in visual deficit: a review
deficits involving colour and motion perception, contrast
sensitivity and visual acuity.22 Primary Open Angle Glau-
coma (POAG) is one of the most common forms of glau-
coma and will be discussed in this review.
Albinism
Albinism is a genetic visual disorder, characterised by a lack
of pigmentation of the eyes and frequently the skin and
hair.23 As a result, the eye does not develop normally, caus-
ing structural differences, particularly hypoplasia of the
fovea.24 Moreover, the visual fibres projecting from the
retina do not decussate normally, but instead, a larger num-
ber (originating from the temporal retina) cross at the optic
chiasm. In normally sighted individuals incoming informa-
tion to each eye is projected to both hemispheres; depth per-
ception and binocular vision both rely on bringing
information from the two eyes together.24, 25 In albinism,
both depth perception and binocular vision are impaired.
Additionally, the lack of pigment within the iris results in an
inability to filter light sources entering the eye, in turn caus-
ing photophobia. Nystagmus – the involuntary and sporadic
movement of the eyes – occurs alongside albinism, in turn
reducing the ability to fixate.26 Strabismic amblyopia is also
reported to co-occur with albinism; this is characterised by
misaligned eyes and can lead to further visual loss and
reduced function if left uncorrected. Given the nystagmus
and foveal hypoplasia, people with albinism also have poor
visual acuity. It is also of note that achiasma, a condition in
which no visual fibres cross the midline, has also been sub-
ject to study with imaging methods.27
Amblyopia
Amblyopia is a neurodevelopmental disorder, characterised
by monocular visual loss, poor visual acuity, and poor con-
trast and spatial sensitivity, as shown in psychophysical stud-
ies.28, 29 It is deemed untreatable once in adulthood, but
various methods have been used to improve the deficits asso-
ciated with the disease. Amblyopia is defined in terms of its
subtypes: (1) Strabismic amblyopia occurs as a result of misa-
ligned eyes (also referred to as a ‘lazy eye’), and can be reme-
died somewhat if surgically corrected early in life, but often
leads to visual deficits nonetheless; (2) Anisometropic ambly-
opia (also known as refractive amblyopia) is caused by a large
mismatch in focus and refractive power between the eyes,
which otherwise appear normal. Less commonly, amblyopia
can arise from visual deprivation as a result of cataract.
Structural MRI
Over the last few decades, advances in MRI technology have
allowed for higher resolution images to be captured, with
better tissue contrast and spatial resolutions <1 mm3. Such
advances have now enabled researchers to explore the pos-
sible relationship between visual deficits and cortical archi-
tecture, particularly within more fine-grained structures
including the lateral geniculate nucleus (LGN) and the
white-matter optic radiations, which may reflect the source
or consequence of the deficit.
Within MRI, there are two types of scans often used to
measure brain structures – T1-weighted and T2-weighted
scans – each of which are strongly dependent on magnetic
relaxation times. Another MRI technique that has gained
popularity recently is diffusion tensor imaging (DTI).
T1-weighted imaging
T1-weighted imaging takes advantage of differences in the
time it takes for protons in different tissue types to realign
with the main magnetic field (longitudinal magnetisation
recovery) following misalignment by a radio frequency
pulse. As each tissue within the brain has its own distinct
T1-relaxation time (due to differences in water concentra-
tion and movement), this generates a high-contrast tissue
gradient on the MR image, which enables different brain
structures to be observed. In T1-weighted images, cere-
brospinal fluid (CSF), with a long T1-relaxation, usually
appears darker compared to the lighter surrounding brain
matter, with white matter (short T1-relaxation) appearing
lighter than grey matter.
T2-weighted imaging
T2-weighted imaging on the other hand is based on differ-
ences in the time it takes for protons in different tissues to
dephase (lose transverse magnetisation). This often pro-
duces the opposite tissue contrast to T1-weighting, whereby
CSF (short T2-decay times) appears lighter compared with
the surrounding brain matter (longer T2-decay). Again, the
opposite relationship is also true for grey and white matter
contrast, with white matter (longest T2-decay) appearing
darker than grey matter.
Diffusion tensor imaging
Another MRI technique that measures brain structure is
DTI (Figure 1). DTI works by measuring the 3-dimensional
displacement of water molecules, typically within white
matter tracts, in which water diffusion is highly anisotropic
due to the movement limitations imposed by neurons, glial
cells, axons and other intra- and extracellular compart-
ments.30 Such measurements can then be used to detect
any changes in tissue microstructure between patients and
control groups. Quantitative outcome measures include
Mean Diffusion (MDi; direction-independent magnitude
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Ophthalmic & Physiological Optics 36 (2016) 240–265
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Using MRI in visual deficit: a review H D H Brown et al.
of diffusion), Radial Diffusivity (RDi; water diffusion coef-
ficient in a direction perpendicular to the axonal fibres) or,
more commonly, Fractional Anisotropy (FA; orientation
coherence of water diffusion). Low FA values are thought
to indicate the presence of axonal disruption and reduced
structural integrity31 while high RDi can indicate myelin
degeneration and glial cell impairment.32
Voxel-based morphometry
Initially, MR images (particularly T1-weighted images)
were largely analysed by measuring the absolute dimension
of brain regions and white-matter tracts based on defining
anatomical landmarks. However, researchers have begun to
examine the local structural composition of individual vox-
els in order to test for intergroup differences in grey matter,
white matter or CSF.33, 34 This analysis technique, known
as voxel-based morphometry (VBM), can highlight both
the extent and location of any structural abnormalities pre-
sent in patients with visual deficits compared to healthy
controls. As a prospective analysis, VBM also benefits from
being hypothesis- and bias-free, examining the whole brain
without limiting the scope of investigation to specific pre-
defined regions of interest (ROIs).
Structural MRI in visual deficits
Anophthalmia and early blindness
Anophthalmic individuals born without fully formed eyes
have been studied anatomically with MRI.4 At the level of
the cortex, only small patches of calcarine cortex exhibited
reduced grey matter volume, whereas larger portions of this
area of the brain exhibited increases in cortical volume. The
largest differences in white matter structure, as assessed vol-
ume of white matter, were observed in the optic tract and
internal capsule. The optic radiation did not differ from nor-
mal in terms of its volume, however its integrity as assessed
by FA was significantly lower than normal.
Research on individuals with early blindness have high-
lighted changes to both white and grey matter structures in
the visual system. Anatomical imaging has highlighted atro-
phy of the optic nerves, chiasm and radiation.35 Consistent
with the anatomical changes in the optic radiation are the
results from DTI studies that also demonstrate atrophy as
well as abnormal connectivity within and between the occip-
ital lobes.36, 37 In addition to the white matter atrophy, corti-
cal atrophy is also evident in early blind patients.38 It is clear
therefore that congenital and early blindness result in struc-
tural changes to the visual pathway. Such changes may
underpin the cross-modal plasticity that is frequently
observed in individuals who are blind at an early age.39, 40
Macular degeneration and retinitis pigmentosa
Structural abnormalities have also been observed in a vari-
ety of hereditary retinal dystrophies, primarily in individu-
als with Stargardt’s disease (a form of JMD) and hereditary
RP.
A recent study by Hernowo and colleagues examined
whole-brain and specific regional differences in both white
and grey matter between JMD adults and healthy aged-
matched controls. Results showed that JMD patients had
bilateral reductions in grey and white matter within visually
associated regions, particularly within the occipital poles
and LGN, and within the optic radiations compared to
controls.41 This supports the idea of transneuronal degen-
eration, whereby the retinal degeneration at the fovea prop-
agates back along the visual pathway and causes atrophy in
the retinotopically corresponding areas of cortex. Interest-
ingly, however, a correlation between disease duration and
grey matter volume was not found, which is unusual con-
sidering the progressive nature of the disease.41
(a) (b) (c) (d) (e)
Figure 1. Diffusion measurements reveal white matter tracts. (a) Coronal section through a typical diffusion weighted data volume; dark areas repre-
sent areas of relatively high diffusion in a single tested diffusion direction. (b) Diffusion measures are routinely taken in multiple directions. A ‘mean
diffusivity’ can be computed by averaging over all diffusion directions as shown in (b); again dark areas represent high ‘mean diffusivity’. (c) This image
reveals how directional, or anisotropic, the diffusion is at any given location; areas of high intensity have a high ‘fractional anisotropy’ (FA) and are
thus biased for diffusion in a specific direction. (d) The false colour map overlaid on the FA image represents the preferred direction of diffusion at
each location; blue colours represent preferred diffusion in the z-plane (superior-inferior), red in the x-plane (left-right) and green in the y plane (ante-
rior-posterior). (e) A zoomed representation of the preferred diffusion direction that can be represented by coloured unit line vectors at each location.
© 2016 The The Authors Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.
Ophthalmic & Physiological Optics 36 (2016) 240–265
243
H D H Brown et al. Using MRI in visual deficit: a review
The studies of individuals with AMD have revealed very
similar findings to those describing JMD. In one study,
Boucard et al. 42 used VBM to analyse T1-weighted MR
volumes and discovered a significant reduction in grey
matter within the posterior region of the occipital lobe in
AMD patients compared to aged-matched controls. In a
larger-scale, multicentre study, Hernowo and colleagues,
examined both whole-brain and regional structure differ-
ences in both AMD and JMD patients. They also found
bilateral reductions in grey and white matter within both
the visual cortex and the optic radiations of the patients.41
This showed there are fairly similar structural differences in
both JMD and AMD compared to controls, which might be
expected given the similarity of visual loss. However,
reduced white matter was also found in the frontal cortex
in AMD patients but not JMD patients. The authors sug-
gest a possible connection between AMD and Alzheimer’s
disease, which is currently being investigated.43–45
Individuals with hereditary RP have also been examined
for structural cortical differences. Kitajima et al.46 found
that the calcarine fissure was increased in width in RP
patients, notably within anterior and middle regions that
normally represent peripheral vision. This corresponds well
with the progression of visual deprivation in RP, which
starts in the peripheral visual field and progresses inwards
towards the fovea. A study by Schoth nearly 10 years later,
however, used DTI measurements and found no difference
in any white matter tract within the visual pathway, includ-
ing the optic nerve and corpus callosum, between RP
patients and healthy controls.47 This may suggest possible
differences between white and grey matter abnormalities,
although more research is needed to decipher this differ-
ence.
Glaucoma
Glaucoma is one of the most heavily studied visual diseases
with respect to MRI structural abnormalities, although the
majority of research has been published within the last
5 years. One of the earliest MRI studies in glaucoma was
conducted by Kashiwagi et al.,48 who found glaucoma
patients (of either primary open-angle or normal tension
subtypes) had a significant smaller optic nerve diameter
and optic chiasm height compared to healthy controls.
More recent studies have also shown smaller optic nerve
and chiasm dimensions in both primary open-angle glau-
coma49 and normal tension subtypes.50 The LGN has also
been shown to be smaller in glaucoma patients using a sim-
ilar method.51 These changes are predicted on the basis of
ganglion cell death, but evidence (reviewed below) also
indicates significant anatomical changes beyond the LGN.
MR imaging has also been used to assess volumetric
changes in both grey and white matter across the cortex.
Using VBM, Boucard et al.42 found that within primary
open-angle glaucoma patients, there were significant grey
matter reductions within the anterior and medial occipital
lobe. These results are in keeping with the idea of retino-
topic-specific atrophy, whereby only the cortical areas that
normally receive input from the damaged part of the retina
experience neuronal deprivation. This concept of specific
regional loss is supported in the same study in MD patients
who, having central-vision loss, show more atrophy in the
posterior occipital lobe.42 Other studies have demonstrated
clusters of grey matter reduction in glaucoma patients,
including bilaterally in calcarine, postcentral and frontal
gyri and unilaterally within the precentral gyrus, middle
frontal gyrus and within the inferior, middle and superior
temporal gyri.49, 52 Additionally, increases in grey matter
were observed bilaterally in the middle temporal, inferior
parietal and angular gyri, and unilaterally within the left
precuneus and left superior parietal and middle occipital
gyri.49 Interestingly, however, Li52 found such grey matter
differences were only significant in severe late-stage glau-
coma and not within the earlier stages where the visual def-
icit was still non-existent or limited. This indicates that the
extent of grey matter atrophy may be dependent on the
level of visual deprivation experienced. However, Williams
et al.53 suggested this relationship might be more complex,
with early-stage glaucoma patients showing increased over-
all volume within multiple cortical areas (21/93 brain areas
studies) compared to healthy controls, while late-stage
glaucoma only showed three larger areas. Nevertheless,
38% of brain regions studied displayed a negative correla-
tion between volume and disease severity, including some
regions unrelated to visual processing. The authors suggest
that the increases in volume during these early stages may
be due to cortical plasticity or be signs of neuronal injury.53
Changes in white matter tissue have also been observed
along the full length of the visual pathway. In patients with
open-angle glaucoma, white matter volume was reduced
bilaterally within the optic nerve, optic tracts, optic chiasm,
optic radiations and LGN. Maximum reductions of 78%
were found in patients in the optic chiasm and minimum
reductions of 16% in the optic radiations compared to
aged-matched controls.54
Diffusion tensor imaging methodology has also been
used extensively to investigate microstructural differences
in visual white matter tracts within glaucoma. Decreases in
FA within primary open-angle glaucoma have been found
in the optic nerve, optic radiations, optic chiasm, optic
tracts and occipital lobe55–62 while increases in RDi and
MDi have been found within the optic radiation, optic
tracts and optic nerve.55–57, 59, 62 The results were replicated
in both normal-tension glaucoma50 and within closed-
angle subtypes.63 Higher FA and lower MDi levels were
found in the optic nerve compared to controls, suggesting
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Ophthalmic & Physiological Optics 36 (2016) 240–265
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Using MRI in visual deficit: a review H D H Brown et al.
that glaucoma patients of different subtypes are likely to
display similar structural changes and reduced integrity
throughout the extent of the visual pathway. A recent
meta-analysis of DTI studies by Li et al.64 confirmed that
there is an overall significant reduction in FA and increased
MDi within the visual white matter pathway in glaucoma
patients.
Interestingly, however, Bolacchi et al.61 found that the
location of increased MDi voxels depended on glaucoma
severity; increased MDi was present only in the proximal
areas of the optic nerve in early-stage glaucoma patients
while both proximal and distal regions were increased in
late-stage glaucoma. A dependence on glaucoma severity
was demonstrated also by Garachi55 and Dai,56 who found
that FA values in the visual pathway correlated negatively
with glaucoma severity while MDi and RDi values corre-
lated positively. White matter changes, as well as changes
found in grey matter by Li52 and Williams,53 indicate that
the severity of glaucoma and corresponding level of visual
deprivation can have a substantial effect on brain structure.
Albinism
The earliest structural MRI study on albinism used T1-
weighted MR images to examine the dimensions of the
white matter visual pathways in adults with albinism.65 The
results indicated that the optic chiasm, optic nerve and cor-
pus callosum all appeared ‘normal’ in size and appearance.
However, these initial findings may have resulted from a
lack of statistical power as more recent literature has largely
found at least some visual pathway abnormalities in
patients with albinism. Schmitz et al.,66 using a similar
method to Brodsky et al.,65 measured and compared the
dimensions of the optic nerve and chiasm within healthy
controls and patients and found that individuals with
albinism had significantly smaller diameters for both white
matter structures. Interestingly, the authors also noted a
visual difference in the shape of the optic chiasm, which
was described as being more like a ‘x’ in appearance rather
than back-to-back brackets ‘)(’ seen in controls. This has
yet to be verified however, using analysis by blind raters
unfamiliar with the participant’s group (control or
patient). Reduced optic chiasm and optic nerve widths have
also been found in other adult cohorts26 similar to the
adults studied by Schmitz.66 Such studies provide evidence
using structural MRI for the atypical crossing of optic nerve
fibres at the chiasm within albinism, indicating clear pre-
LGN abnormalities.
Post-LGN structural differences, both in grey and white
matter, have also been examined in albinism using MRI.
Using T1-weighted images, Neveu et al.67 found that the
calcarine sulcus in individuals with albinism was signifi-
cantly smaller in length, depth and surface area compared
to healthy controls. Visual cortex abnormalities have also
been found by von dem Hagen et al.26 who, in addition to
measuring the optic nerve and chiasm, also used VBM to
examined differences in both grey and white matter
between individuals with albinism and controls. Their
results showed a significant decrease in grey matter volume
confined to the occipital pole, while no difference in white
matter volumes was observed. Reduced grey matter in indi-
viduals with albinism has also been shown in the posterior
ventral-occipital cortex, which also displayed reduced gyri-
fication.68 The reduced grey matter in the occipital poles
around posterior V1 was attributed to reduced ganglion cell
number in the foveal area, due to the underdevelopment of
the fovea in albinism.
Interestingly, however, Bridge et al. 68 also reported
increases in grey matter volume within the superior frontal
gyrus and calcarine sulcus, along with an increase in corti-
cal thickness within posterior V1 in individuals with albin-
ism. They theorised that a lack of synaptic pruning within
selective cortical areas during development resulted in an
increased volume and thickness.
Amblyopia
More than other visual deficits, there is currently a wealth
of research studying structural brain abnormalities within
children suffering from amblyopia. This is not entirely sur-
prising, as amblyopia has long been considered a largely
cortical phenomenon. Xiao and colleagues compared grey
matter volume using VBM in children with either strabis-
mic or refractive anisometropic subtypes. Results showed
several clusters of reduced grey matter in the left-hemi-
sphere middle frontal gyrus, parahippocampal gyrus and
inferior temporal gyrus as well as bilaterally in the calcarine
cortex within both amblyopic subtypes compared to
healthy controls.69 Similar results have also been found
more recently in amblyopic children, who display clusters
of reduced grey matter (left-hemisphere postcentral gyrus
and inferior occipital gyrus and bilateral parahippocampal
gyrus) and white matter volumes (left-hemisphere cal-
carine, right-hemisphere precuneus and bilateral inferior
frontal areas) compared to control children.70 Nevertheless,
unlike other studies Li et al. (2013) also demonstrate an
increase in white matter volume within the right-hemi-
sphere middle occipital and cuneus areas and within the
left-hemisphere orbitofrontal region. Such increases are
thought to represent neuronal plasticity, possibly driven by
input from the unaffected eye, resulting in an increase in
volume to compensate for the loss of visual input within
other areas. Given this result contrasts with other studies
this interpretation is quite speculative. Indeed, DTI studies
have also revealed microstructural abnormalities within the
white matter, with significantly lower FA in the optic
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H D H Brown et al. Using MRI in visual deficit: a review
radiation of amblyopic children compared to healthy chil-
dren,70, 71 particularly in the posterior region,71 suggesting
reduced structural integrity. Similar indications of reduced
structural integrity have also been found more recently in
amblyopic adults, who show an increased MDi in the optic
radiations, vertical occipital fasciculus, corpus callosum
and inferior longitudinal fasciculus.72, 73
MRI and VBM analysis have also been used to examine
structural differences between amblyopic children (with
either strabismic or anisometropic subtypes) and their
adult counterparts, who were presumably never offered
corrective treatment or were treated unsuccessfully as chil-
dren. Mendola et al.74 found that, similar to the studies
mentioned above, child amblyopes showed reduced grey
matter clusters within the visual cortex, specifically in the
calcarine and paracalcarine cortices, ventral temporal cor-
tex and both the medial and lateral parietal-occipital junc-
tion. Anisometropic subtypes also displayed further
reductions in grey matter compared to strabismic subtypes,
who only displayed significant reductions within the right
hemisphere. Similarly, adult amblyopes of both subtypes
showed reduced grey matter clusters, although less wide-
spread and severe compared to the amblyopic children,
although the authors state this could be explained by dis-
crepancies in disease severity arising from recruitment dif-
ferences between the two groups.
Similarly, Chan et al.,75 again using VBM on MRI data,
discovered decreased grey matter clusters within both visual
and non-visual cortical areas in adults with strabismic
amblyopia. This included the calcarine sulcus bilaterally,
the intraparietal sulcus, lingual gyrus and cuneus, as well as
unilaterally in the superior occipital gyrus and inferior pari-
etal lobule. An increase in grey matter was also observed in
the orbitofrontal, frontal, precentral and anterior cingulate
regions, again suggesting the possibility of compensatory
cortical plasticity effects similar to those found in white
matter by Li within children.70 Furthermore, this also sug-
gests that higher order visual areas, in addition to the pri-
mary areas, may be equally affected by amblyopia.
However, a study by Barnes found that while there was sig-
nificant decrease in grey matter of the LGN, there was no
difference observed in either the occipital or temporal lobes
between amblyopic adults and controls,76 in contrast to
results reported by Xiao69 and Mendola.74 It is possible that
the different outcomes in the two studies may be accounted
for by methodological differences – while Barnes examined
differences in grey matter concentration in functionally-
defined regions, the other studies examined volumetric
changes in anatomically-defined areas.
In another study, Lv et al.77 used structural MRI to mea-
sure differences in regional cortical thickness and found
there was no significant difference in either global thickness
or regional thickness in primary or secondary visual cor-
tices (V1 and V2) between amblyopes and healthy controls.
Nevertheless, patients did show additional hemispheric dif-
ferences in cortical thickness compared to controls,
although the direction of these differences was not stated.
What role could structural MRI play in the future?
On the whole, research demonstrates that disorders of the
eye and visual pathways can have a significant effect on
the structural architecture of both grey and white matter in
the brain. Both pregeniculate and postgeniculate differences
have been revealed within anophthalmia, early blindness,
albinism, amblyopia, JMD, AMD and glaucoma, while
postgeniculate differences have been observed in RP. Inter-
estingly, such differences are seen not only throughout the
visual pathway but also within some areas seemingly unre-
lated to vision. Furthermore, it is important to note that
throughout this literature, there are seeming contradictions
in that both increases and decreases in grey matter can be
observed within the same condition. Such differences have
often been attributed to a wide range of mechanisms
including cortical plasticity,49, 53, 70, 75 alterations to synap-
tic pruning68 and neuronal damage.53 However, these are
currently only speculative with no definitive explanation on
what such grey matter changes actually represent in terms
of structural changes within the brain.
One potential avenue for future MRI research that could
shed further light on these mechanisms is to use a longitu-
dinal design to assess the progression of structural abnor-
mality in the posterior visual pathways in relation to
deterioration of vision or structure in the anterior aspects
of the visual pathway. In the case where retinal damage pre-
cedes cortical damage, this would support the idea that
structural changes may be directly caused by either loss of
functional visual input or through anterograde trans-
synaptic degeneration, where cell death in the retina
spreads to connecting neurons to reach different areas of
cortex. There is clear evidence for anterograde and retro-
grade degeneration in the visual system from visual loss
due to both eye enucleation and occipital lobe lesioning,
respectively.78–84 MRI has the capacity therefore to inform
on the timing of such changes resulting from visual loss.
Another potential use for MRI techniques is as a screen-
ing method to guide medical management, whereby corti-
cal structural abnormalities could indicate the severity of
visual disease or indeed catch it in its earliest stages. Along
these lines, a study by El-Rafei et al.85 attempted to define a
detection mechanism within glaucoma using a classifica-
tion system constructed from DTI structural data in the
optic radiations. The system was able to discriminate
between glaucoma patients and controls with 94.1% accu-
racy and between normal-tension and open-angle glau-
coma subtypes with 92.8% accuracy. This approach
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Using MRI in visual deficit: a review H D H Brown et al.
therefore opens up the intriguing possibility of a high per-
formance MRI detection system that could accurately
detect the presence of visual disease and possibly replace
retinal-based methodology. However, El-Rafei did not
report the severity of glaucoma patients used; structural
differences may only be capable of detecting severe cases,
and may only be useful in confirming what ophthalmologi-
cal techniques had already established, although at a signifi-
cantly higher monetary cost. Indeed, very few glaucoma
studies identified differences between healthy controls and
level 0 stage glaucoma (increased intra-ocular pressure but
no visual loss), although some did find structural differ-
ences between controls and level 1 (early-stage glau-
coma).55 Therefore, while structural MRI may be suitable
for assessing severity, it may be unsuitable for early detec-
tion of visual diseases, at least for glaucoma.
Structural MRI can also be valuable in guiding the
potential direction for treatments and in predicting patient
visual outcome after treatment. Although there is currently
no cure for many visual diseases, recent treatments have
focused on restoring retinal function, through gene ther-
apy,86, 87 stem cell therapy88 and retinal prosthetics.89, 90
However, there may be a risk to restoring retinal function if
brain structure has changed significantly enough to alter
the visual pathways and the processing of retinal inputs.
Structural MRI may therefore offer a way to determine
whether retinal treatments would be effective on a patient-
by-patient basis, whereby those with significantly altered
cortical structure may not benefit from treatment as much
as those with greater visual system integrity. Additionally,
structural MRI may be beneficial in the development of
neuroprotective treatments,91 to target the primary areas of
neuronal changes and to limit the level of degeneration/at-
rophy particularly in early stages of visual loss.
In addition to assessing medical treatments, alternative
treatments such as behavioural training can be examined
through the use of structural MRI. Within AMD, Rosen-
garth et al.92 examined the effect of oculomotor training, a
common training technique to improve peripheral fixation
in those with central vision loss, on brain structure. They
found a significant increase in both grey and white matter
in the posterior cerebellum compared to those who under-
took either no training or vision-unrelated memory train-
ing. While not treating the condition in the same way that
medical treatments do, such training might still improve
patient independence and increase quality of life.
Magnetic resonance spectroscopy
Magnetic resonance spectroscopy (MRS) is a technique that
allows the chemical composition of the human brain to be
measured. As the name suggests the measurement derives a
spectrum of resonances that contains peaks at specific fre-
quencies reflecting the different chemicals in the sample. In
broad terms, the height of the peaks yields a measure of
chemical concentration. Though MRS can be performed
using a variety of nuclei, including carbon (12C), nitrogen
(14N), fluorine (19F) and sodium (23Na), only the nuclei
phosphorus (31P) and hydrogen (1H) exist in vivo in con-
centrations high enough for routine clinical evaluation.93
Proton (1H) MRS studies have increased in popularity due
to the high natural abundance of protons and their elevated
sensitivity to magnetic manipulation, better spatial resolu-
tion, relative simplicity of technique as well as a shift of
interest to areas of metabolism that lack phosphorylated
metabolites.94 1H-MRS can be obtained with most MRI
systems without additional hardware, provided field homo-
geneity of the tissue is optimised via a technique known as
‘shimming’.
There are two types of 1H-MRS: single voxel spec-
troscopy (SVS), which receives the spectrum from a single
voxel only or chemical shift imaging (CSI), which measures
spectra in projection (1D), on a slice (2D) or a volume
(3D). In general, the technique assesses a relatively large
(>=8 cm3) volume of interest (VOI) in order to maximise
signal-to-noise ratio. Consequently, a large VOI can present
problems as it may include heterogeneous tissue types as
well as CSF. The inclusion of CSF in large voxels is particu-
larly problematic in older participants whose sulci and ven-
tricles become enlarged as part of the natural aging process,
an issue to bear in mind when investigating metabolic
changes in older populations.
The spectrum
1H-MRS data are usually presented as line spectra rather
than the two-dimensional images produced by MRI exami-
nations (Figure 2). The peaks on the spectra correspond
with various metabolites found within the VOI. The x-axis
denotes the chemical shift frequency quantifying the
metabolite in parts per million (ppm), and the y-axis plots
the relative signal amplitude or concentrations of the vari-
ous metabolites. Spectra are read from right to left, with
the numbers (ppm) on the x-axis increasing in the same
direction.
Choline (Cho) represents the total amount of cytosolic
choline and is considered a metabolic marker of membrane
density and integrity. A decrease in Cho concentration sug-
gests a reduction in cell density, a delay in cell renewal and
damage to the signal transport system in neurons.
Creatine (Cr) is known to play an important role in
energy metabolism. On the spectrum, the Cr peak actually
represents the sum of Cr and phosphocreatine. Tissue
death is accompanied by a gradual reduction in Cr, along
with other metabolites. In several degenerative diseases,
however, Cr concentration levels appear to remain constant
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H D H Brown et al. Using MRI in visual deficit: a review
throughout the brain. Due to the assumed stability of Cr,
clinical evaluations incorporate Cr in order to calculate
metabolic ratios such as NAA:Cr and Cho:Cr. However in
the research setting, absolute metabolic quantities are mea-
sured to increase the sensitivity and specificity of MRS, and
regional and individual variability in Cr concentrations
have been reported.94
c-aminobutyric acid (GABA), Glutamine (Gln) and Glu-
tamate (Glu) spectral signatures are challenging to isolate.
Both Gln and Glu (frequently assessed in MRS in the Glx
peak) play a role in detoxification and regulation of neuro-
transmitters. Glu is the most abundant excitatory neuro-
transmitter in the brain whereas GABA is the principle
inhibitory neurotransmitter. Fortunately, there are meth-
ods that can obtain GABA specific measurements from
MRS, incorporating J-difference editing95 with the MEGA-
PRESS sequence96–98 (Figure 3).
In terms of brain plasticity, it is believed that GABA is
involved in a homeostatic balance between excitatory, inhi-
bitory and modulatory pathways, as shown in animal mod-
els of visual disease and visual recovery. This balance
mediates developmental and adult plasticity across multiple
time scales.99 The balance can be shifted towards excitation
with up-regulation of modulatory cholinergic pathways.
Similarly, an increase in GABA can shift this balance
towards inhibition.100
Reduced resting GABAergic inhibition has been shown
to trigger ocular dominance plasticity, modulating both the
onset and offset of the critical period. Therefore, measuring
GABA in response to visual stimulation following depriva-
tion could be a sensitive indicator of plasticity. Short-term
monocular deprivation changes the balance between the
two eyes, boosting perception in the deprived eye, reflecting
homeostatic plasticity, in which neurons attempt to regu-
late their own excitability to compensate for sudden
changes in input. A study by Lunghi et al.101 demonstrated
that monocular deprivation also induces a concomitant
reduction in resting GABA specific to primary visual cor-
tex. This confirms that GABAergic mechanisms for homeo-
static plasticity can be demonstrated by combining MRS
with psychophysical measures of eye dominance.
myo-Inositol is a simple sugar with a peak at 3.56 ppm.
In the brain, myo-inositol is synthesised primarily in glial
cells and cannot cross the blood-brain barrier, and is con-
sidered a glial marker. An increase in myo-Inositol concen-
tration is thought to represent glial proliferation or an
increase in glial cell size, both of which can occur in inflam-
mation. Myo-Inositol has also been labelled as a breakdown
product of myelin.
N-acetylaspartate (NAA) is found at relatively high con-
centrations in the human brain parenchyma and is particu-
larly localised within neurons and related to neuronal
processes. NAA appears as the highest peak in the normal
spectrum, resonating at 2.02 ppm. With good resolution,
second and third peaks of NAA can be observed at 2.6 and
2.5 ppm.94 NAA is produced in the mitochondria of neu-
rons and transported into the neuronal cytoplasm. A
decrease in NAA concentration is routinely considered an
indicator of neuronal loss or dysfunction, as such decreases
are mostly observed at the moment when a disease is in
progress.
Figure 3. GABA-edited spectrum produced from a MEGA-PRESS
sequence using the processing tool GANNET. The GABA-edited data is
represented by the blue line with the model of best fit represented in
red. The black line below represents the residual between the model
and the data.
Figure 2. Normal MR spectrum showing the chemical shift in parts per
million (ppm) for the metabolites myo-Inositol (Ins), choline (Cho), cre-
atine (Cr), GABA, Glutamate, Glutamine complex (Glx), N-acetylaspar-
tate (NAA) and lipids.
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Using MRI in visual deficit: a review H D H Brown et al.
MRS in visual deficits
MRS is an inherently quantitative technique since the signal
intensity of a resonance is directly proportionate to a speci-
fic metabolite concentration. MRS data can therefore be
analysed in conjunction with MRI to correlate anatomical
and physiological changes in the brain. For this reason,
MRS is a potential tool for studying the metabolic changes
in visual cortex in vivo, providing direct clinical applica-
tions for studying brain plasticity and adaptive changes
following sight loss.102
To enable effective correlations between MRI and MRS
data, it is important to understand any chemical changes
that occur in the brain due to the natural aging process,
and differentiate them from those occurring as a result of
visual disorders. Studies reveal that generally, concentra-
tions of normal metabolites vary slightly with age.94 On the
whole, by the time a child is 2 years old the spectral pattern
will be similar to that of an adult. As the brain matures, the
concentration of NAA increases and the concentration of
Cho decreases. In the elderly, however, there is a normal
decline in NAA.94 By taking natural changes due to aging
into account, observed changes in metabolic concentration
measured in individuals with sight loss can be attributed to
the disorder itself.
Anophthalmia and early blindness
Early blindness is a useful model system for understanding
developmental plasticity, as it has been established that
when a sense is absent from early life, brain regions usually
associated with that particular sense are often recruited by
the remaining modalities, a process termed cross-modal
plasticity.103, 104
Cross-modal responses and higher levels of functional
connectivity105 have been found within occipital cortex of
early blind individuals. Yet it remains unclear how these
cross-modal changes in functional responsiveness occur-
ring in early blind individuals are mediated. One hypothe-
sis states that changes within occipital cortex in the
inhibitory, excitatory and neuromodulatory biochemical
pathways drive the changes in functional responses.106
Work on animal models has clearly shown that the bal-
ance between excitatory and inhibitory neurotransmitters
can govern the level of plasticity in the cortex.107 Using1H-MRS to examine the effects of metabolic concentrations
in occipital cortex in early blind individuals, a study
revealed increased concentrations of myo-Inositol, Cho and
Cr and decreased concentrations of GABA.106 There were
no significant changes in NAA or Glu concentrations. From
this, it was concluded that fundamental changes to occipital
biochemical pathways occur as a result of cross-modal
responses in early blindness.106 However, further work is
needed to reconcile these changes with the theoretical
framework that can be used to explain how plasticity is
underpinned by neurochemical changes.
Anophthalmia is a form of congenital blindness; how-
ever, it is not yet clear whether anophthalmia can be
thought of as an extreme form of early blindness or
whether this disease results in a unique phenomenology.108
Studying the effects of visual deficit in this group of indi-
viduals is ideal as anophthalmia is not associated with any
other neurological impairment. Therefore, investigations in
anophthalmia can reveal the effects of complete visual
deprivation on healthy brain tissue. Although research has
shown large-scale structural and functional reorganisation
of visual cortex as a result of anophthalmia,109, 110 the neu-
rochemical changes underlying cross-modal plasticity
remain unclear.109 Incorporating both MRS and MRI, dif-
ferences in structure and metabolite concentration were
investigated in the pericalcarine cortex in anophthalmic
patients.109 Results revealed elevated levels of Cho, Cr, Gln,
Glu and myo-Inositol relative to sighted controls. Elevated
metabolite levels also correlated with significantly greater
proportions of grey matter volume. This elevation in meta-
bolic concentration could reflect a shift toward enhanced
plasticity or sensitivity that might mediate or unmask
cross-modal responses.109
In cases of both early and congenital blindness, research
has highlighted evidence of cross-modal plasticity, whereby
brain regions are recruited by other areas to process infor-
mation. MRS has been integrated with MRI research to
show changes that occur chemically as a result of this cross-
modal response. Investigations confirm there is a funda-
mental change in metabolic concentrations within occipital
cortex, including increased levels of Cho, Cr and myo-Ino-
sitol, suggesting possible markers of enhanced plasticity.
Glaucoma and AMD
Retinal damage is in continuous progress in glaucoma and
AMD. A number of mechanisms have been invoked to
explain the effects of glaucoma, including reactive oxygen
species, excitotoxicity, defective axon transport, trophic
factor withdrawal and loss of electrical activity.111 These
pathophysiological actions lead to a series of biochemical
compound changes in brain tissue. For example, trans-
synaptic damage caused by excitotoxicity of Glu (as can be
assessed by Glx levels) is an important mechanism of glau-
comatous central visual pathway injury. Using MRS to
investigate metabolic concentrations in the striate area and
geniculocalcarine tract, significant decreases in NAA:Cr
and Cho:Cr were detected, although there were no reported
differences in concentrations of Glx:Cr in a group of glau-
coma patients compared with sighted controls.112 These
results suggest that within the central visual pathway in
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H D H Brown et al. Using MRI in visual deficit: a review
glaucoma, neurodegeneration is an ongoing process. If pro-
gressive visual deprivation affects the metabolism of the
adult visual brain, lower concentrations of the metabolite
NAA would be expected in occipital cortex, given the asso-
ciation between NAA and neuronal activity. However, one
study reported no difference in either Cho, Cr or NAA
absolute concentrations in the striate area in a group of
glaucoma patients compared to AMD patients, relative to
sighted controls.113 This indicates that within the visual
pathways of the brain, progressive retinal visual field defects
do not always induce a measurable decrease in metabolite
concentration.
A single MRS VOI can in theory be positioned any-
where in the brain as long as there is limited interference
with the metabolic signal. One theory proposed as a fac-
tor in glaucoma is the apoptosis theory (programmed cell
death). Therefore, one would expect to see an increase in
metabolic concentrations of Glu in the vitreous humour
and lateral geniculate body (LGB) regions due to the
known neurotoxic effects of Glu. MRS was performed
using a VOI in these two regions in a group of glaucoma
patients. Analysis revealed significantly greater levels of
Glx:Cr in both VOIs for the glaucoma patients compared
to sighted controls, supporting the apoptosis theory in
the aetiopathogenesis of glaucoma.114 MRS could there-
fore move the diagnosis of glaucoma forward enhancing
the understanding and diagnosing of glaucoma at the
cellular level114.
Summary and future directions for MRS
It is clear that there is a future from MRS in examining the
visual system in those with visual deficits. Cross sectional
studies have and will shed light on which chemical con-
stituents change in the brain as a result of brief and long-
standing visual deprivation. It will also be important to use
GABA as a valuable marker of plasticity and take the
opportunity to follow such changes over time. The use of
higher magnetic field strengths may ultimately improve
quantification of metabolite concentrations within the
brain and this in turn could help us understand the neuro-
chemistry of visual loss and how it can be harnessed and
ameliorated.
Functional MRI
In addition to its ability to investigate structural and chem-
ical information about the brain, MRI also enables
researchers to non-invasively acquire images of the active
brain.115 Functional magnetic resonance imaging (fMRI)
has quickly become one of the primary techniques used in
cognitive neuroscience research, allowing us to investigate
how different parts of the brain respond to a given
stimulus, and determine how different functions are repre-
sented in the brain.
FMRI takes advantage of changes in blood oxygenation
levels, and is exploited as a physiological marker of brain
activity.116 The blood oxygenation level dependent (BOLD)
contrast is used to measure the relative amounts of oxy-
genated and deoxygenated haemoglobin that will vary
across the brain depending on the amount of neuronal
activity within local regions. This difference in signal in the
brain can be measured by acquiring T2*-weighted images.
T2*-weighting is related to T2-weighting, but incorporates
the additional dephasing effect of the external environment
on T2 relaxation times. In sum, an increase in neural activ-
ity in a brain region results in a local change in oxygenated
haemoglobin, followed by an increase in blood flow to the
region, resulting in a local increase in BOLD signal. Visu-
ally, this creates an MR image that is brighter in active
regions.117, 118
With regard to vision research, fMRI has been widely
used to measure how the brain maps our visual field, and
determine how this varies between individuals in health
and disease. Before neuroimaging was available,
Holmes119 outlined key features of how visual space is
represented in human visual cortex using brain lesions
caused by gunshot wounds. Neuroimaging research has
supported his original findings, demonstrating that visual
cortex is topographically organised; spatial information is
preserved, meaning neighbouring areas in the visual scene
are represented by neighbouring neurons in visual cor-
tex.120 Moreover, the brain contains multiple maps of
visual space, including ‘early’ visual areas V1, V2 and V3.
Early visual cortex occupies the medial wall of the occipi-
tal cortex; primary visual cortex (V1) occupies the cal-
carine sulcus, with V2 and V3 bordering V1 both dorsally
and ventrally. The central part of our visual field (where
visual acuity is highest) is located at the occipital pole
and has a much larger representation in visual cortex; this
is referred to as cortical magnification. Elsewhere in the
visual pathway, the lateral geniculate nucleus (LGN)
mediates information coming in from the retina, project-
ing it to V1. Beyond V1, other visually responsive regions
take on higher level processing, for example face and
object recognition.1
New technologies, such as MR-compatible eye tracking
systems have also allowed researchers to track eye move-
ments and fixation stability in participants. Those with eye
disease involving the fovea have difficulty in keeping the
eyes fixed on a target in comparison to normally sighted
individuals. Eye movements will in turn affect the fMRI
data acquired, as stimuli may fall on a different part of the
visual cortex in participants with unstable fixation; there-
fore, when mapping out visual field representations in
visual cortex, eye movements could be a confounding
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Using MRI in visual deficit: a review H D H Brown et al.
factor.121 Giving participants a simple fixation task will
improve attention and in turn improve fixation stability.
Functional MRI in visual deficits
Beyond the eye itself, research has shown that after losing
sight through retinal damage or disease, regions of cortex
dedicated to processing parts of the visual field no longer
receiving input are subject to change.24, 25, 122–126 There is a
debate in the literature regarding the definition of cortical
reorganisation, but also the mechanism by which it occurs,
if at all.127 Cortical reorganisation can refer to structural
changes in the brain, but more frequently, it refers to func-
tional changes whereby patterns of neural activation differ
from those observed in healthy individuals. We have pro-
posed that reorganisation should be used only when it is
clear that the absence of visual input, combined with the
known properties of the normal visual system, cannot
explain the pattern of activity observed in patients with
visual loss.127, 128
It has become clear, however, that in addition to oph-
thalmological measures, such as visual acuity, perimetry,
optical coherence tomography and physical examination of
the retina, fMRI can aid our understanding as to how the
entire visual pathway is affected with eye disease, from
retina to cortex.124, 125, 129, 130 This will undoubtedly aid
further work investigating ways to safely restore vision.
Typically, fMRI studies include a variety of stimulus
types and tasks to tease apart different functions and there-
fore access information about specific parts of the visual
pathway. Retinotopic mapping stimuli are commonly used
to define visual maps in the brain.131–134 In the travelling-
wave method, also known as phase-encoded mapping132
participants view two types of flickering checkerboard stim-
uli: an expanding ring which measures eccentricity (degrees
from central fixation), and a rotating wedge which mea-
sures polar angle, the dimension that runs orthogonal to
that of eccentricity.131–133 Each stimulus is presented in
multiple cycles to cover a portion of the visual field and
scans are averaged for wedge and ring stimuli in order to
increase BOLD signal-to-noise ratio.135 As ring stimuli
expand and eccentricity increases, activity travels posterior
to anterior in the occipital lobes; representations of central
vision reside in the occipital pole whereas the periphery is
represented in anterior visual cortex (Figure 4). Boundaries
between each early visual area (separate retinotopic maps)
are identified using reversals in polar angle representa-
tions131, 132, 134 (Figure 4). Retinotopic maps are consis-
tently identified across participants, but can vary in size
and anatomical location across individuals.1
(a) (b) (c) (d) (e) (f) (g)
Figure 4. Retinotopic mappings in individuals with eye disease. In each panel, an inflated rendering of the occipital lobe (a magnified version of the
area highlighted by the broken line in the hemisphere shown to the left) of the left hemisphere is illustrated. Superimposed on the occipital lobes in
false colour are the visual field locations that the brain represents. In each panel the colour coding of the visual field location is given above the visuali-
sations of the brain maps. In (a) and (b), the map of polar angle and eccentricity in a control are given. Polar angle is used to determine boundaries
between visual field maps. The eccentricity maps of this control participant are adapted in panels (c–e) to schematise the results observed in individu-
als with retinal scotomas. In panel (c) a schematic map of eccentricity is shown for a rod achromat alongside, in panel (d), a schematic of a control
viewing under scotopic conditions. The broken circle highlights where differences in the map were found; the rod achromat has activity that extends
more posteriorly than in the control indicating that the visual cortex has reorganised. In (e), the schematic eccentricity map for an individual with Age-
related Macular Degeneration, in which no evidence of large-scale reorganisation is shown. In f and g, the eccentricity maps obtained for stimulation
of the nasal (f) and temporal (g) retina of the right eye of an individual with albinism are given. Stimulation of the nasal retinal of the right eye pro-
duces a map that is very similar to that derived from controls. In contrast to controls however a large representation of the ipsilateral visual field is seen
when the temporal retina of the right eye is stimulated. The maps show that a given cortical location responds to equal, but opposite eccentricities.
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H D H Brown et al. Using MRI in visual deficit: a review
More recently, population receptive field mapping (pRF)
has been used to acquire further information about visual
field maps, by modelling the neural response to a variety of
stimuli at different positions in the visual field. This allows
researchers to estimate the average receptive field size of
neurons within a voxel, as well as the mean location repre-
sented within the visual field.136 Studies reviewed here do
not cover pRF methods; however it is of note that this
method is increasingly being used in fMRI research.
In addition to visual field mapping techniques, investiga-
tors have examined ‘resting state’ fMRI data that allow
visual organisation to be probed even in visual regions of
the brain that no longer receive or have never received
visual input. As the name suggests, resting state scans do
not require participants to complete a task or attend to
visual stimuli, and so the BOLD response is observed whilst
participants are at rest, providing information about corti-
cal regions as well as functional connectivity.137 Many stud-
ies have used this technique to assess visual field maps in
both normally sighted individuals and clinical populations,
to discern whether visual representations change as a result
of disease. In some instances, retinotopic mapping is not
feasible and so other stimuli are used to assess the state of
visual cortex; this will be discussed later in relation to eye
disease.
Anophthalmia and early blindness
Cases of anophthalmia and early blindness are valuable
particularly when discussing reorganisation.138 In order
to fully understand how the visual system develops both
structurally and functionally, it is important to study
individuals who have no visual experience. It has been
shown that the organisation of visual cortex, from V1
through to object-related areas fusiform face area (FFA)
and parahippocampal place area (PPA), are retained in
individuals with early blindness and anophthalmia.110, 138
By assessing eccentricity, laterality and elevation – the
three main components of retinotopic mapping – the
functional connectivity within visual regions could be
investigated in the blind. Interestingly, functional connec-
tivity MRI revealed very similar functional divisions in
the blind group and the sighted group, thus suggesting
that visual input is not fundamental for the development
of functional connectivity.138
The functional development of visual areas seems to
occur through the use of different sensory modalities, such
a sound and touch.139, 140 By examining resting state as well
as anatomical connectivity, research has shown that con-
nectivity between the corpus callosum splenium and V1
bilaterally remain intact in individuals with early blindness
or anophthalmia.141 Furthermore, the occipital lobe
in these individuals appears to be incorporated into a
functional network for processing language and sounds.110
It has been shown that when performing an auditory nam-
ing task whereby participants were required to name words
described prior, anophthalmics demonstrate greater activity
bilateral lateral occipital cortex (LOC) and left V3a when
compared to sighted controls. V1 however was activated by
any sound, including reversed speech.110 This suggests
that further into the visual hierarchy, despite processing
auditory stimuli, the functional hierarchy remains
whereby low level visual areas do not show stimulus
preferences, but higher visual areas do. In addition, the
calcarine sulcus, posterior temporal, LOC and V5 (a
motion processing area) were activated bilaterally by
simple tone stimuli.140 In addition to increased occipital
activity, a reduction in temporal lobe activity was
observed in anophthalmics in response to tones.140 Over-
all, individuals with anophthalmia showed more activity
within visual cortex to sound.
Studying blindness allows researchers to determine to
what extent visual experience aids the formation and devel-
opment of the visual system. Recent findings suggest that
the development of retinotopic organisation is not neces-
sarily driven by retinal waves (action potentials that sponta-
neously propagate across of the retina before the
development of photoreceptors) or visual experience, hence
organisation being maintained in anophthalmia.141 Overall,
evidence from studies including individuals with early
blindness and anophthalmia suggests that visual cortex
maintains its retinotopic organisation despite having no
visual input.
Macular degeneration
One issue currently under debate within vision research is
whether patients with macular degeneration show cortical
reorganisation, as a result of losing central vision bilaterally.
There is evidence to suggest cortical reorganisation occurs
but the mechanism by which this occurs is inconclusive;
some researchers have shown that the region of primary
visual cortex formally representing the fovea, referred to as
the lesion projection zone (LPZ), takes on a new function
and processes visual information from the intact peripheral
retina.123, 124, 126, 142 Some argue that the region of visual
deficit must be absolute and include the fovea in order to
generate reorganisation, because some patients with foveal
sparing do not exhibit reorganisation.124 Additionally, the
spread of activation in the LPZ is not always large-scale; in
some cases, only part of the occipital pole is activated by
stimuli presented to a small, intact part of the retina, sug-
gesting a smaller, more local reorganisation is occurring in
these individuals.142
After losing central vision, MD patients naturally develop
a preferred retinal locus (PRL) in part of the peripheral
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retina that is still intact. Typically, a PRL will develop in a
region abutting the scotoma, but the location depends on
the size and extent of the damaged retina.143, 144 It is
thought that the establishment of a PRL may trigger reor-
ganisation, as it essentially takes on the function of the for-
merly intact fovea.143 However, while some participants
exhibit LPZ activity to a greater extent for stimuli presented
to the PRL compared to a peripheral location of equal
eccentricity (‘non-PRL’),143 others have argued there is no
difference between peripheral locations.126 Any subtle dif-
ferences between the PRL and non-PRL are thought be dri-
ven by attention.126
In contrast, some researchers, who used retinotopic
mapping methods, report a lack of reorganisation in
patients with MD and JMD as no discernible activity was
detected in the LPZ in all cases.122, 125, 145 This contrasts
with the remapping of retinal input revealed in retintopic
mapping experiments on rod achromats, who have a small
central scotoma at birth146 (for comparison see the
schematics in Figure 4). The absence of remapping in the
patients with AMD and JMD was also confirmed by mod-
elling the expected cortical responses on the basis of the
retinal scotoma.125 A lack of reorganisation may be positive
news with respect to treatment restoring retinal function; if
cortex has not taken on a new role it is theoretically ready
to resume processing incoming information (although see
earlier sections on the atrophy of the LPZ).
It is also of note that the ‘resting state’ activity in the LPZ
has been probed to understand how visual organisation
might change in this zone which no longer receives
input.147 This adds weight to the idea that the organisation
of the visual cortex is largely unchanged by a partial
removal of input, consistent with the organisation found in
individuals, who have no visual input from birth.4, 110
Other studies have investigated apparent activity in the
LPZ in terms of feedback from extrastriate visual areas.129,
130, 148 Using multiple stimulus types (including faces,
checkerboards, drifting contrast patterns) in two different
conditions; a one-back task and passive viewing, stimulus-
synchronised responses were apparent within the LPZ in
75% of participants when performing a task. Under passive
viewing conditions, stimuli elicited zero or negative
responses in the LPZ.129 Task-dependent activity in the
LPZ was also shown in patients with RP.130 The authors
suggest that LPZ activity might represent the unmasking of
a normal feedback mechanism from extrastriate regions,
due to task demands. However, age-matched, normally-
sighted control participants did not exhibit responses in the
unstimulated region in either passive or task conditions. Li
et al.,148 refer to this feedback mechanism as a form of
functional reorganisation.
The majority of research described above includes both
forms of MD, both age-related and juvenile. Research has
shown that while qualitatively JMD and AMD are quite
similar regarding neural responses and extent of reorgani-
sation, the size of the silent part of the LPZ is noticeably
smaller in JMD, even when scotoma size is accounted
for.148 It is assumed that in MD, the visual system devel-
oped typically prior to disease onset. The slight difference
between may represent the time course of plasticity and
emphasise that earlier onset allows for increased plasticity.
Visual hallucinations are a common symptom of Charles
Bonnet Syndrome, found to co-occur with MD in some
cases. It is worth noting that fMRI has also been used to
investigate the possible neural mechanisms underlying this
symptom,149–151 however this beyond the scope of this
review, and so it will not be discussed further.
Glaucoma
Structural changes have been observed as discussed previ-
ously, but comparatively fewer studies have examined the
functional changes associated with glaucoma.152, 153 As
with all eye diseases, it is important to understand how the
brain is affected, in accordance with behavioural and per-
ceptual deficits. The following studies explore both bilat-
eral22, 153, 154 and unilateral22, 155, 156 glaucoma. In bilateral
cases, the fellow eye is often less affected than what authors
refer to as the glaucomatous eye. Animal work has previ-
ously shown a multitude of changes associated with glau-
coma, including neurochemical modulations in the ocular
dominance columns for both the affected and the unaf-
fected eye, a reduction in GABA levels which in turn causes
reduced inhibition and thus a greater response to the unaf-
fected eye in cortex.155 The question has been raised as to
whether fMRI can provide evidence of cortical reorganisa-
tion in patients with glaucoma, and determine to what
extent of functional plasticity occurs. FMRI studies have
used various checkerboard stimuli to map visual cortex in
glaucoma132, 134, 153, 156; standard retinotopic mapping is
not always ideal because the representation of scotoma in
early visual cortex can be difficult to map accurately and so
a template fitting approach has been adopted using static
checkerboard stimuli.153, 157 Other stimuli used (static or
with contrast reversal) include full field checkerboard,
radial checkerboards occupying a hemifield22, isopter (arc),
‘bow tie’ and ‘hourglass’ shapes (comprising checker-
boards) to map the scotoma, and vertical and horizontal
meridians respectively.22, 153, 156 Using these methods,
studies have reported a reduction in the BOLD response
within V1.153, 156 Monocular testing revealed similar maps
for the glaucomatous and the unaffected eye, with match-
ing numbers of active voxels, however responses were
weaker in contrast to the unaffected eye.22, 156 The biggest
reduction of the BOLD response occurred whilst stimulat-
ing the glaucomatous eye with high contrast stimuli; this
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Ophthalmic & Physiological Optics 36 (2016) 240–265
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H D H Brown et al. Using MRI in visual deficit: a review
may suggest a particular deficit in the parvocellular path-
way, however direct investigation is required to address this
question.156 The results highlight the sensitivity of fMRI in
detecting the scotoma and corresponding cortical
responses. Despite the change in the magnitude of the
response, which can be explained by reduced visual acuity,
the fact the organisation and general size of the maps do
not change significantly between the eyes suggests a stable
functional organisation in visual cortex in patients with
unilateral glaucoma.156
Functional magnetic resonance imaging is an important
tool for glaucoma research as the disease in known to
extend beyond the eye; fMRI responses have been shown to
correspond to the extent of visual loss and correlate with
standard ophthalmological measures such as perimetry.22
Understanding these global changes is important particu-
larly because there is evidence to suggest that different types
of glaucoma impact on cortex differently. Previous studies
focussed on patients with primary open angle glaucoma
(POAG), but a study on normotensive glaucoma found no
discernible change in functional activity in visual cortex.154
Overall, this will inevitably improve our understanding of
the disease and the mechanism underlying the functional
deficits, alongside any structural abnormalities.
Albinism
Research in both animals and humans has shown dysfunc-
tion in the visual pathway of individuals with albinism
expressed as an abnormal crossing of retinal fibres.23–26,
158–163
Monocular stimulation in participants with albinism
reveals that the representation of the nasal retina matches
that of normally sighted control participants, yielding
responses in the contralateral hemisphere.23–25, 163 How-
ever, cortical responses to temporal retinal locations are
abnormal. The same regions in visual cortex contralateral
to the stimulated eye respond to the temporal retina, as well
as nasal retina24, 25 (Figure 4). Additionally, as eccentricity
increases, ipsilateral regions take over and representations
of temporal retina begin to resemble those of healthy
sighted controls again.24 This suggests the representation of
the temporal and nasal retinal is mirrored and a single
voxel is processing two parts of the visual field of compara-
ble eccentricity. As referred to above, the cortical represen-
tation reverts to normal at a specific eccentricity – the line
of decussation. It has been shown that the shift in the line
of decussation is linked to the pigmentation level in indi-
viduals with albinism.164
The standard method of diagnosing albinism involves
measuring visually evoked potentials.26, 161, 165 Using full
field stimulation, deficits regarding hemispheric lateralisa-
tion were observed, whereby the hemisphere contralateral
to the eye being stimulated responded more strongly.26 The
spatial resolution of fMRI appears to allow albinism to be
detected with greater sensitivity and specificity.26 In the
case of albinism, therefore, diagnosis may be improved with
the addition of fMRI. Researchers have shown fMRI
responses to full field stimulation highlight differences in
lateralisation of responses between albinism and controls
(healthy sighted and individuals with nystagmus). How-
ever, responses to hemifield stimulation are similar between
groups with albinism and those with nystagmus, but when
restricted to the most posterior slices of the occipital lobe, a
group difference emerged.26
It is also interesting to note that a rare condition, achi-
asma, meaning that no descussation of the visual fibre
occurs, results in very similar cortical organisation patterns
to those found in albinism.166, 167
Amblyopia
Amblyopia has been studied extensively as its neural basis
is still a source of debate. The advantage of studying ambly-
opia in particular is that it allows for the examination of
reorganisation within the visual pathway which is depen-
dent on experience.77 Multiple neuroimaging studies have
demonstrated that V1, extrastriate cortex and the LGN are
affected in amblyopia.168
Striate cortex (V1)
Researchers initially debated whether deficits in V1 were
the source of behavioural deficits observed.168–170 V1 com-
prises ocular dominance columns, made up of neurons that
respond to input from one eye, or the other. Previous work
in animals demonstrated that amblyopia results in a shift in
ocular dominance, suggesting that the deficit is under-
pinned by changes to the brain.171, 172 However, early
human post-mortem studies showed no evidence of
anatomical changes in ocular dominance columns.173, 174
More recent work in humans utilising fMRI have informed
on this debate. Stimuli consisting of sinusoidal gratings,
drifting at high contrast are ideal for exciting visual cor-
tex.175, 176 An early fMRI study in humans examined
changes in ocular dominance columns, and found more
voxels representing the unaffected eye.176 This study also
examined differences between early and later onset ambly-
opia, however this is a controversial finding and further
investigation is still required.
Further work has been conducted to map out visual
cortex in both strabismic and anisometropic amblyopes,
using standard retinotopic mapping procedures described
previously121, 177 to map visual representations in each eye
independently.121 A reduction in fMRI signal was observed
in representations of the amblyopic eye, compared to the
unaffected eye; however this result was not consistent
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Using MRI in visual deficit: a review H D H Brown et al.
across participants. While on average amblyopes demon-
strated a larger difference in ocular dominance compared
to controls, they also showed a smaller region of cortex rep-
resenting either eye.
To determine if subtypes of amblyopia have differential
effects on visual cortex, studies have examined responses to
various checkerboard stimuli, manipulating the size and
number of reversals to tease apart the differences.170, 178
Results indicate that in strabismic amblyopes, there is a
reduction in activity within the calcarine sulcus in response
to stimuli of lower spatial frequency. In contrast, ani-
sometropic amblyopes show a reduction in calcarine activ-
ity in response to high spatial frequencies.170 Most studies
do not report a significant difference between subtypes and
therefore combine participants for analysis.29, 77
Extrastriate
While many studies have focussed on the effects of ambly-
opia on early visual areas by stimulating the eye with simple
achromatic pattern stimuli,169, 175, 176 it is important to
assess deficits extending into extrastriate visual areas.179
Behavioural measures have not been shown to correlate
with activity in striate cortex in amblyopia, suggesting per-
haps deficits correlate with activity in higher visual areas.121
Face and scene processing have been investigated in both
strabismic and anisometropic amblyopes but results show
no significant differences between types of amblyopia.180
Under monocular viewing conditions, a decrease in activity
in face-related cortical areas was evident in response to
faces when viewing with the affected eye, but no such defi-
cit was shown in building-related cortical areas in response
to building stimuli. Poor visual acuity in the amblyopic eye
and the fact that viewing faces requires processing of finer
details may explain why patients appear less proficient at
face processing as well as reduced neural responses in face
processing regions.181, 182 Behavioural testing of the ambly-
opic eye also demonstrated a larger deficit in identity recog-
nition and to a greater extent, facial expressions,
performing better with naming and categorising building
stimuli.180 However, given that neural responses to build-
ing stimuli also appear normal, suggests a specific deficit
within the ventral stream.177, 179 The higher level deficit is
also dependent on the size and position of the stimulus;
when smaller stimuli were presented to the amblyopic eye,
the deficit remained, however for larger stimuli, responses
were more similar to those observed with the unaffected
eye179 This was apparent in V1 through to V4 and also in
the posterior fusiform gyrus.
In addition to ventral stream abnormalities, research
has revealed a deficit in V5/MT in ambylopes, suggest-
ing the dorsal stream is also compromised in ambly-
opes.183–185 Global motion deficits have primarily been
tested psychophysically, however fMRI studies have also
shown reduced activation in motion areas. Ani-
sometropic amblyopes show reduced activity in V5 as
well as V3a, which authors suggest is not attributed to
poor visual acuity or blurring, as control participants
did not show a deficit in motion processing areas fol-
lowing monocular blurring or by decreasing the lumi-
nance.185 Strabismic amblyopes also show a similar
deficit but to a greater extent that anisometropic, partic-
ularly for the high-level random dot kinematograms.183
The cause of this reduction in motion areas is not clear
however structural imaging has shown a reduction in
grey matter in amblyopes.74 It is also of note that the
areas recruited when processing motion are no different
between the amblyopic and non-amblyopic eyes, it is
the magnitude of the response within motion areas that
differs.184
The studies above do not rule out the possibility that the
observed deficits in higher visual areas are the result of defi-
cits in earlier visual areas. In addition to examining
responses in different visual areas following eye disease, it is
important to establish if the areas themselves are affected
or whether it is the connections between areas where the
deficit occurs.186 The effects of amblyopia have been inves-
tigated in terms of both dorsal and ventral processing,
focusing on the connectivity between striate and extrastri-
ate visual areas. ROIs included the LGN and V1 to V4 (de-
fined retinotopically).186 In addition to establishing the
degree of connectivity, researchers can assess directional
effects along the thalamo-cortical pathway. Table 1 sum-
marises the directional effects within visual cortex.186 Any
significant reductions in activity have been indicated with a
downward arrow. Overall there is a significant reduction in
feedforward and feedback connectivity for the amblyopic
eye. A significant reduction in feedforward connectivity
between the LGN and V1 was observed, particularly in the
ipsilateral hemisphere, whereas feedback connectivity was
impaired in both hemispheres.186
When V1 was excluded from analysis, connectivity was
still significantly reduced in both hemispheres overall, sug-
gesting that any V1 changes may not fully account for the
deficit. Overall, the study demonstrated that when the
amblyopic eye is stimulated, there was a significant impact
on both feedforward and feedback connectivity within the
visual pathway, in both the dorsal and ventral streams.
The change in connectivity correlated with behavioural
deficits, but did not correlate with the fMRI signal in
visual regions.
Lateral geniculate nucleus
The role of the LGN in amblyopia has been explored to
determine whether deficits are apparent earlier in the
visual pathway.29, 152 The LGN can be localised using both
structural and functional imaging; showing participants
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Ophthalmic & Physiological Optics 36 (2016) 240–265
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H D H Brown et al. Using MRI in visual deficit: a review
checkerboard stimuli of high contrast allows for functional
localisation. A reduction in LGN activity was observed in
all participants for both hemispheres when the amblyopic
eye was stimulated, relative to the unaffected eye. However
there were no hemispheric differences when viewing with
the amblyopic eye or the unaffected eye.29 Similar
responses across hemispheres suggest there is no difference
with regard to the input to the LGN.29 This work is
important as it stresses that deficits are not restricted to
cortex. Given that the LGN plays an important role in the
development of vision, it is possible that its role in ambly-
opia is simply that it does not moderate the visual system
in the typical manner.187 It is yet to be determined
whether the deficits observed in the LGN are a result of
local influences within the LGN itself, or whether it is a
result of abnormal connectivity with cortex.29, 186
Amblyopia is deemed untreatable in adulthood. How-
ever, different therapies are being investigated to alleviate
some of the deficits. Levodopa has been piloted as a poten-
tial treatment for amblyopia.188, 189 Another approach is to
apply transcranial direct current stimulation (TDCS) to
visual cortex28. We acknowledge that there is ambiguity
within the literature regarding the effectiveness of therapies;
however, it is beyond the scope of this review and therefore
will not be discussed. In the case of any treatment, however,
it would be valuable to use fMRI (and potentially other MR
methods) to provide visual cortical biomarkers of treat-
ment outcome.
Conclusions
This review has examined how magnetic resonance imaging
(MRI), including structural, spectroscopy and functional
scans, has been utilised to investigate a selection of visual
disorders. Structural MRI has revealed abnormalities in
grey and white matter density across both visual and non-
visual areas in conditions including amblyopia, albinism,
glaucoma and macular degeneration. Structural MRI has
been used in numerous studies particularly in glaucoma,
where a reduction in visual pathways has been detected.
Studies have shown similar reductions in grey and white
matter in the posterior occipital lobe and optic radiations
in both age-related macular degeneration (AMD) and juve-
nile macular degeneration (JMD). Patients with AMD also
displayed reduced white matter in the frontal cortex, sup-
porting the association between AMD and Alzheimer’s dis-
ease. Although there have been relatively few studies on RP,
studies have shown deterioration within anterior and mid-
dle occipital lobe but have not revealed any abnormalities
earlier within the visual pathway. The overriding conclu-
sion therefore is that the visual cortex undergoes changes
following loss of functional inputs. It remains to be seen
whether the changes are permanent and irreversible, which
may impact on treatments for visual restoration. It will also
be important to assess what the nature of the atrophy is –
does it involve cell death and or significant rewiring. Cur-
rent methods are unlikely to inform on these issues as yet,
but future research in this area is important.
MR Spectroscopy is at an earlier stage than MR imag-
ing approaches in terms of assessing visual deficits. How-
ever, the research in this area has yielded some important
preliminary observations. Importantly, the recent
advances in measuring GABA – a key neurotransmitter
that plays an important role in vision and cortical plastic-
ity – will provide new and important ways to investigate
visual deficits.
Table 1. Reduction in connectivity in dorsal and central processing streams in amblyopia, as shown by Li et al.186 Downward arrows indicate signifi-
cant reduction in connectivity
Connection Ipsilateral hemisphere Contralateral hemisphere
LGN ? V1 ↓
LGN V1 ↓ ↓
Connection
Ventral stream Dorsal stream
Ipsilateral hemisphere Contralateral hemisphere Ipsilateral hemisphere Contralateral hemisphere
V1 ? V2 ↓ ↓ ↓ ↓
V2 ? V4 ↓
V1 ? V4 ↓ ↓
V1 V2 ↓
V1 V4 ↓ ↓
V2 V4 ↓ ↓
V1 ? V3a ↓
V2 ? V3a ↓
V1 V3a ↓
V2 V3a ↓ ↓
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Ophthalmic & Physiological Optics 36 (2016) 240–265
256
Using MRI in visual deficit: a review H D H Brown et al.
Functional MRI provides evidence of extensive func-
tional changes throughout the visual pathway as a result
of vision loss. It is still not entirely clear if functional
reorganisation occurs with AMD and JMD, or whether
activity within the lesion projection zone, representing
the scotoma, is a result of normal feedback mechanisms,
mediated by task demands.123, 125, 129 Relatively fewer
studies examine the functional changes in glaucoma, but
the evidence that there are silent areas in visual cortex
representing the scotoma, provide little indication of
cortical reorganisation. In albinism, abnormal retino-
geniculate projections do not appear to reorganize,
instead reorganisation is likely at a synaptic level to
allow for the normal and abnormally projecting infor-
mation to co-exist in cortex.24 The visual pathway is
affected significantly in amblyopia, irrespective of sub-
types. As well as specific deficits within LGN, V1 and
extrastriate areas, investigations of amblyopes reveal evi-
dence of reduced functional connectivity, including both
feedforward and feedback mechanisms.29, 186
Besides informing on the way in which different diseases
affect the visual pathway, from retina through to visual cor-
tex, MRI could be used to aid diagnosis, and determine the
potential course and efficacy of treatments. Although there
is currently no cure for the majority of visual diseases,
recent treatments have focused on restoring visual function
via a variety of approaches (stem cell therapy, gene therapy,
retinal prostheses, etc.). However, the success of retinal
restoration depends on the extent to which the rest of the
visual pathway function and structure have remained stable
from the point sight was lost, without any significant
degeneration or reorganisation. MRS could also be incor-
porated to predict successful restoration of vision by mea-
suring levels of inhibitory neurotransmitters before
treatment. If there is evidence of reorganisation, functional
or structural, this will impact how the new information
entering the retina is processed in all elements of the visual
system.
By examining functional activity, researchers can deter-
mine whether changes are occurring and over what time
course. MRI can therefore be used to determine whether
retinal treatments would be effective on a patient-by-
patient basis, perhaps excluding those with significantly
altered cortical structure that may not benefit from the
treatment. Additionally, structural MRI may also be used
to guide the development of neuroprotective treatments,91
which could be used to target the primary areas of neuronal
changes, potentially limiting the level of degeneration par-
ticularly in early-stages of visual loss. Finally, MRS shows
great promise as an assay for detecting biomarkers indicat-
ing plastic or degenerative changes associated with visual
disease.
Acknowledgements
The authors acknowledge with thanks Fight for Sight pro-
ject grant (1523/1524), the Wellcome Trust for its Institu-
tional Strategic Support Fund, awarded to the University of
York, and the Medical Research Council (G0401339).
Disclosure
The authors report no conflicts of interest and have no pro-
prietary interest in any of the materials mentioned in this
article.
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Holly Brown is a Research Associate in the Department of Psychology at the
University of York, where she was awarded a BSc in Psychology in 2013 and
an MSc in Cognitive Neuroscience in 2015. Holly’s research focuses on visual
processing and the organisation of visual cortex in health and disease. Using
techniques such as structural and functional MRI as well as neurostimula-
tion, Holly’s current work focuses on patients with macular disease.
© 2016 The The Authors Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.
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H D H Brown et al. Using MRI in visual deficit: a review
Rachel Woodall is a Research Associate in the Department of Psychology at
the University of York. Following successful completion of an MSc degree in
Cognitive Neuroscience, Rachel began her current role in 2015. Her main
research interests focus on the functional organisation of visual cortex fol-
lowing damage and disease using neuroimaging techniques including MRI
and MR Spectroscopy.
Rebecca E. Kitching is a PhD Student in the Department of Psychology at
the University of York, where she recently graduated first in her class with a
BSc degree in Psychology. Her current research involves the use of EEG and
both functional and structural MRI in order to investigate clinical and non-
clinical populations.
Heidi Baseler is a Lecturer in Imaging Sciences in the Centre for Neuro-
science in the Hull York Medical School, based at the University of York.
With a first degree in Biology/Psychology from Dartmouth College, USA,
she went on to obtain a PhD in Vision Science from the University of Cali-
fornia Berkeley School of Optometry. With an Individual Postdoctoral
Training Fellowship from NIH, she studied magnetic resonance imaging
techniques at Stanford University and went on to consult at the Smith-Ket-
tlewell Eye Research Institute, USA. She uses magnetic resonance imaging
and non-invasive electrophysiology of the human retina and brain to investi-
gate neural plasticity in the visual system following vision and hearing loss.
© 2016 The The Authors Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.
Ophthalmic & Physiological Optics 36 (2016) 240–265
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Using MRI in visual deficit: a review H D H Brown et al.
Tony Morland is Professor of Visual Neuroscience in the Department of
Psychology and the Head of Neuroscience in the Hull-York Medical School.
He read Physics at Imperial College, London, UK and stayed there to study
for his PhD on deficits in human colour vision. His postdoctoral studies on
visual dysfunction continued in London in collaboration between Imperial
College and the Medical Research Council’s Human Movement and Balance
Unit. In 1997 he was awarded a Wellcome Trust Research Career Develop-
ment Fellowship that allowed him to travel to Stanford University, where he
learned fMRI techniques for assessing visual cortical function. He has used
these techniques to investigate how the visual areas of the brain are orga-
nized in health and disease.
© 2016 The The Authors Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.
Ophthalmic & Physiological Optics 36 (2016) 240–265
265
H D H Brown et al. Using MRI in visual deficit: a review
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